Human cytomegalovirus (HCMV) is a beta-herpes virus that can establish persistence and latent infections. HCMV can cause morbidity and mortality in immuno-compromised individuals such as transplant-recipients and HIV-infected persons. In fact, HIV-positive patients are at risk of HCMV-related blindness. HCMV is also a major infectious cause of birth defects in newborns causing hearing disturbances and mild forms of mental retardation. Selective pressure by the immune system on viruses has resulted in their ability to generate evasive tactics to avoid immune detection. HCMV expresses proteins that modulate both the innate and adaptive branches of the immune system. Cellular immunity appears to be the main target of HCMV with an emphasis on interfering with CD8+ cytotoxic T cell (CTL) activation. HCMV encoded gene products from the unique short region of the genome US2, US3, US6 and US11 interfere with CTL recognition of HCMV-infected cells by preventing the surface expression of major histocompatibility complex (MHC) class I molecules. This strategy would limit the frequency of CTLs directed against HCMV epitopes during the early phase of HCMV infection and allow HCMV to escape immune detection. US2 and US11 target class I molecules for proteasomal degradation. Recent evidence suggests that US2 may also target the MHC class II DRalpha and DMalpha molecules for proteasomal degradation. This suggests that US2 is an important gene in the HCMV repertoire of viral proteins that modulates the immune system. To that end, we will define the specific regions of US2 responsible for targeting MHC class I molecules for destruction as well as identify the cellular proteins that facilitates the degradation process. We will mimic the early phase of HCMV infection and determine the function of US2 in the context of other viral gene products such as US3 and US11. A full understanding of how HCMV US2 manipulates the cellular machinery of the host to prevent MHC class I and class II antigen presentation may permit the design of pharmaceutical agents that block US2 function.